Efficient esterification of carboxylic acids with alkyl halides catalyzed by fluoride ions in ionic liquids

Article abstract of DOI:10.1016/S0040-4039(03)01693-9

Ionic liquids based on 1,3-dialkylimidazolinium methanesulfonate have been used as efficient reusable reaction media in the esterification of several carboxylic acids with alkyl halides catalyzed by fluoride ions. The method has wide applicability, and it is mild and green; it is useful for the protection of acids, via ester formation, for alkali labile molecules.

Full text of DOI:10.1016/S0040-4039(03)01693-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6583–6585
Efficient esterification of carboxylic acids with alkyl halides
catalyzed by fluoride ions in ionic liquids
L. Brinchi, R. Germani and G. Savelli*
Department of Chemistry, Universita` di Perugia, Via Elce di Sotto, 8, 06124 Perugia, Italy
Received 16 June 2003; revised 7 July 2003; accepted 7 July 2003
Abstract—Ionic liquids based on 1,3-dialkylimidazolinium methanesulfonate have been used as efficient reusable reaction media
in the esterification of several carboxylic acids with alkyl halides catalyzed by fluoride ions. The method has wide applicability,
and it is mild and green; it is useful for the protection of acids, via ester formation, for alkali labile molecules.
© 2003 Published by Elsevier Ltd.
As part of a wide research program aimed at investigat-
ing structure–properties relationships for novel ionic
liquids (IL), we have recently reported1 our results
about the preparation of new systems, as 1,3-
dimethylimidazolinium (MMIM) and 1-butyl-3-
ethylimidazolinium (BEIM) methanesulfonates (Scheme
1). The use of ionic liquids has recently received much
attention for a series of advantages over organic sol-
vents, such as low vapor pressure, recyclability, high
thermal stability and ease of handling, other than the
fact that ionic liquids often can act as catalysts and not
only as reaction medium. All these properties make
these systems very good candidates for application in
developing environmentally benign chemical processes,
and, nowadays, ILs are widely used as greener alterna-
tives to classical volatile organic solvents in chemical
transformations.2 Our systems, BEIM and MMIM,
have features quite useful for their use as reaction
media. They have an inert anion, and are easy of
handling; they are liquid at moderate temperature (ca.
room temperature for BEIM and 82°C for MMIM);
they are insoluble in a wide range of solvents useful for
extraction such as n-hexane, diethyl ether, ethyl acetate,
and this makes the work-up procedures quite easy. In
fact, although by GC/MS analysis quantitative yields
may be reported, actual isolated yields are often signifi-
cantly lower, and mixtures of solvents have to be
carefully searched for a satisfactory extraction of prod-
ucts.3 Furthermore, these IL are prepared with a proce-
dure that avoids several drawbacks often encountered
in synthesis of ionic liquids, such as the use of large
excess of toxic organic solvents, the separation of by-
products, heat supply for several hours.2 Our proce-
dure, already published,1 gives a high yield of IL in
short time, without any by-product; it doesn’t make use
of energy supply because reaction itself, exothermic,
provides the necessary heat; it is simple involving only
one step. Moreover, the procedure has recently been
improved with respect to that published, and now ethyl
acetate is used as solvent, instead of toxic 1,1,1-
trichloroethane.
Scheme 1. 1,3-Dimethylimidazolinium methanesulfonate
(MMIM) and 1-butyl-3-ethylimidazolinium methanesulfonate
(BEIM).
In our recent work, we used BEIM and MMIM as
efficient systems for the esterification of carboxylates
with alkyl halides, in mild conditions, with facile isola-
tion of products and reuse of the reaction media.1
Although this reaction has interesting uses, it has no
applicability if the substrate has functional groups
labile to alkaline conditions. Therefore, herein we
report our results about the use of the same ionic
Keywords: ionic liquids; esterification; carboxylic acid; nucleophilic
substitution; fluoride ion.
* Corresponding author. Tel.: +39-075-5855538; fax: +39-075-
5855538; e-mail: savelli@unipg.it
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/S0040-4039(03)01693-9

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L. Brinchi et al. / Tetrahedron Letters 44 (2003) 6583–6585
acid systems in a polar aprotic solvent such as DMF there
is a very strong H-bond between the fluoride the anion
and the acid hydroxy-proton.6 This H-bond directs
electrons from the electron-rich fluoride anion to the
organic part of the complex, activating the nucleophile.
These salts allowed the preparation of several kinds of
esters, using DMF as solvent.5,7 However, a solvent such
as DMF has operational inconveniences and other sys-
tems are being looked for: for instance, more recently,
activation by fluoride ions has been achieved under
solid–liquid phase-transfer conditions in THF8 and by
the system CsF–Celite in CH3CN.9
Scheme 2. Esterification of carboxylic acids with an alkyl
halide.
liquids as reaction media to carry out esterification of
carboxylic acids by reaction with alkyl halides. This
reaction represents a fundamental transformation in
organic synthesis, especially important when considering
protection of the carboxylic acids,4 and alternatives to
the most common method which makes use of dia-
zomethane are important, because the high toxicity of
this reagent excludes large-scale operations. The main
problem is the activation of the nucleophile. Clark et al.
showed KF and also CsF to be effective in activate this
reaction:5 in fact they showed that in fluoride-carboxylic
Herein we report the use of ionic liquids as reaction
media for esterification of carboxylic acids with alkyl
halides in presence of KF (Scheme 2). This reaction
medium should allow solubilization of both fluoride salt
and organic molecules, and has several advantages over
the use of organic solvents such as THF, DMF and
CH3CN. The procedure we developed is operationally
Table 1. Esterification of carboxylic acids with alkyl halides in ionic liquida

L. Brinchi et al. / Tetrahedron Letters 44 (2003) 6583–6585
6585
simple, fast safe, and allows reuse of the reaction
medium.†
recently been shown that this reaction is also activated
using KF in ionic liquids, but conditions are quite
different from ours, because the ionic liquid was not the
reaction medium, but was used with a large excess of
acetonitrile and water.10
Table 1 summarizes the results of non-optimized condi-
tions for reactions of alkyl halides with a variety of
carboxylic acids and shows that the desired esters were
generally obtained in excellent yields, usually bigger than
95%. Yields reported are based on GC analysis; but yields
by weight were also evaluated (with complete extraction
of the products) and were quantitative like the GC data.
The structure of esters obtained was confirmed by NMR.
The procedure gives similarly excellent results both in
excess or in defect of the acid. The second case is useful
for protection of the carboxylic group. Both ionic liquids
(MMIM and BEIM) gave good yields and we therefore
used extensively MMIM, which is cheaper, and easier to
handle.
In the absence of the ionic liquid as reaction medium,
reactions do not proceed. We tried reactions in the
presence of KF and without ionic liquid, and also in ionic
liquid but without KF. In the first case, reactions of
liquid PhCH2Cl with both liquid acetic acid (the mixture
is heterogeneous, but can be magnetically stirred), and
solid benzoic acid (the mixture is quite heterogeneous,
and cannot be magnetically stirred) were tried, and no
reaction occurred in either case in the experimental
conditions that give quantitative yields in the presence of
ionic liquid. In the second case, we also tried both kinds
of acids (acetic and benzoic), and in this case, no reaction
occurred in the experimental conditions that give quan-
titative yields in the presence of KF.
The procedure was successfully tested with several car-
boxylic acids. Aliphatic acids give good yields, be they
liquid (acetic, trimethylacetic, butyric, entries 1–4), or
even solid ones, with quite a long chain (entries 5, 6), but
in this case a slightly longer reaction time is required to
obtain a high yield. Also, dicarboxylic acids are success-
fully used (adipic acid, entry 7), provided that a factor
of 2 was considered in the ratios of the reagents and of
the IL: the reaction time used was 3 h. Acids containing
aromatic moiety such as phenylacetic (entry 8), trans
cinnamic (entry 9), benzoic and some of their derivatives
(entries 10–12) give also excellent yields.
Furthermore, after reaction, it was possible to reuse the
IL in a further run: after extraction with diethyl ether,
the ionic liquid is dried under vacuum (to eliminate traces
of the solvent) and simply reused.
We think that this new approach for the synthesis of
esters and protection of carboxylic acids offers many
advantages over classical procedures. Our method does
not require the use of alkali at any stage, provides high
yield in short times, can be accomplished under mild and
safe conditions, without volatile solvents and the reaction
medium can be recycled. The method has proven to have
validity in defect of the acid, and is useful for protection
purposes, even in multifunctional molecules eventually
alkali-labile. We are currently investigating the extension
of this method to multifunctional molecules, including
the objective of regio- chemo- and stereoselectivity.
The amount of ionic liquid used, as reaction media is
generally small, the ratio of IL/acid is 5. The ratio
KF/acid is also small, 2: attempts to lower it to values
smaller than 2 reduced the yield (entries 3, 4). As the alkyl
halide, we generally used benzyl chloride, but we also
tried p-bromo-phenacyl bromide (entry 13); both are
useful and widely used in protection routes. In all cases,
the halogen exchange reaction (ClꢀF) is limited to <2%,
as shown by results from GC analysis. However, it has
References
1. Brinchi, L.; Germani, R.; Savelli, G. Tetrahedron Lett.
2003, 44, 2027.
† Procedure for esterification in an ionic liquid. In a dried (in oven at
120°C) 4-ml vial, a mixture of ionic liquid and the carboxylic acid
was magnetically stirred for ca. 15 min until the acid was dissolved.
Potassium fluoride, dried at 200°C and thereafter kept in the
presence of P2O5, was then added under nitrogen. The mixture was
then heated to 90°C (the mixture is not perfectly homogeneous, but
fluid) and magnetically stirred for 10–15 min and the alkyl halide
was added. The mixture was stirred for the required time. After ca.
1 h the mixture became quite viscous and heterogeneous. At the end
of reaction, after cooling to room temperature, tBu–benzene was
added, as internal standard; water was then added, and the mixture
was extracted with diethyl ether (3×10 ml). The combined organic
extracts were washed with sodium bicarbonate, dried over Na2SO4,
and analyzed by GC. When yields by weight were determined, no
internal standard was added at the end of reaction, and the organic
solvent was eliminated from combined extracts by rotatory evapora-
tion. After reaction, it was possible to reuse IL in a further run:
after extraction with diethylether, the ionic liquid was dried under
vacuum (to eliminate traces of the solvent), and benzoic acid and
benzyl chloride reloaded, but no KF was reloaded. This reuse gave
60% yield by weight of benzyl benzoate. This process has to be
optimized, as regards reaction time, and because of problems arising
from heterogeneity of the reaction mixture during the second run.
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